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BET Bromodomain Inhibition Results in the Conserved Upregulation of Sirtuin 1
Author(s) -
Jones Lipinski Rachel,
WyniaSmith Sarah,
Nord Joshua,
Smith Brian
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04110
Subject(s) - bromodomain , brd4 , sirtuin , sirtuin 1 , downregulation and upregulation , histone , histone deacetylase , biology , bet inhibitor , sirt3 , chemistry , epigenetics , acetylation , biochemistry , cancer research , microbiology and biotechnology , gene
Sirtuin 1 (Sirt1), an NAD + ‐dependent histone/protein deacetylase, functions in response to inflammatory, metabolic and oxidative stressors. Decreased Sirt1 protein levels and enzymatic activity are associated with diseases of chronic inflammation including neurodegeneration, diabetes and obesity; therefore, drugs that enhance either Sirt1 expression and/or enzymatic activity have promise as treatments for inflammation‐related diseases. Bromodomains are epigenetic readers that bind acetyl‐lysine residues on histones and other nuclear proteins. Of particular interest are the four bromodomain and extraterminal domain (BET) proteins (Brd2, Brd3, Brd4 and Brdt) which have emerged as potential targets to treat a broad spectrum of illnesses, including diabetes, cardiovascular disease and chronic kidney disease. Here, we show that treatment of pancreatic β‐cells with BET bromodomain inhibitors leads to increased Sirt1 protein levels in a time‐ and concentration‐dependent manner. This upregulation of Sirt1 protein was observed in a variety of human cell lines (breast cancer, hepatocytes and adrenal), and was observed after treatment with structurally distinct BET bromodomain inhibitors. We found that Sirt1 transcript is also upregulated after BET bromodomain inhibition in a time‐ and concentration‐dependent manner and that the increase in Sirt1 transcript is observed regardless of the BET bromodomain inhibitor used. ChIP‐seq studies suggest that BET bromodomain inhibitors do not directly bind the promoter region of Sirt1. Work is ongoing to determine if the observed increase in Sirt1 protein also increases Sirt1 enzymatic activity by examining the acetylation status of p53, a downstream substrate of Sirt1. To determine which BET protein is responsible for the observed increase in Sirt1 expression, we are using CRISPR‐Cas9 knockout cell lines and silencing RNA knockdowns of Brd2, Brd3 and Brd4. To summarize, BET bromodomain inhibitors provide a means of increasing Sirt1 protein levels in diverse mammalian cells indicating that BET bromodomain inhibition may provide a novel treatment for diseases where increased Sirt1 protein and/or activity is protective, including diabetes, cardiovascular and neurodegenerative diseases.